DESCRIPTION (Verbatim from the applicant's abstract) Pulmonary and other organ failure syndromes have emerged as leading causes of morbidity and mortality for trauma patients with otherwise survivable injuries. An important step in the evolution of this inflammatory disorder is the migration of neutrophils into the interstitium and the subsequent generation of oxidants. This results in extracellular matrix destruction and cytotoxicity. Neutrophil recruitment is induced and regulated by a family of proteins termed chemokines. Neutrophils possess two classes of chemokine receptors. CXCRI is specific for IL-8 and GC-2 whereas CXCR2 is a promiscuous CXC chemokine receptor. Our data indicate that CXCR2 activation suppresses subsequent neutrophil responses, and that this occurs in a highly ligand-specific manner. The responses studied include chemotaxis to IL-8 and adherence-dependent production of H202 in response to TNFa and other secretagogues. We believe that neutrophils encounter a sequence of chemokines, including platelet-released NAP-2, and endothelial and epithelial derived IL-8, GROor, and ENA-78. We have found that CXCR2 ligation by NAP-2 suppresses the migration to IL-8 while allowing continued responses to oxidative stimuli. Conversely, CXCR2 ligation by GROa suppresses oxidant production but allows continued IL-8 directed migration. In studies of trauma patient neutrophils, we have found a heightened oxidative responsiveness and diminished CXCR2 receptor expression. This is associated with a loss of suppression of oxidative activity by R2 ligands. In the current project, we will study mechanisms controlling expression of CXCR2. We will study the mechanisms for ligand-specific signaling, which we believe due (for oxidative suppression) to inhibition of an integrin-activated Src kinase. We will continue our studies of neutrophils from severely injured patients to further define the bases for the heightened oxidative responsiveness seen and examine the fate of CXCR2 in these cells. Finally7 we will explore the role of chemokine dimerization as a mechanism for ligand specific signaling. Together, these studies will define potential points for therapeutic intervention and provide important insight into regulation of the acute inflammatory response.